Pancreatic β-Cells Express the Fetal Islet Hormone Gastrin in Rodent and Human Diabetes

Dahan, Tehila; Ziv, Oren; Horwitz, E. P.; Zemmour, Hai; Lavi, Judith; Swisa, Avital; Leibowitz, Gil; Ashcroft, Frances M.; Veld, Peter In’t; Gläser, Benjamin; Dor, Yuval

doi:10.2337/db16-0641

Cited by 55 publications

(73 citation statements)

References 42 publications

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“…The incidence of double-hormone positive cells was proposed to increase in type 2 diabetes, and to represent a new mode of beta cell failure in which beta cells lose their identity or dedifferentiate [32]. Consistent with this suggestion, we have recently reported that, in type 2 diabetes, a subset of pre-existing beta or delta cells induce the expression of the fetal islet hormone gastrin [33]. In addition, deletion of key transcription factors in adult beta cells leads to the appearance of beta cells co-expressing insulin and other hormones, or even converting entirely to other cell types [34–36].…”

Section: Multihormonal Islet Cellsmentioning

confidence: 79%

Beta cell heterogeneity: an evolving concept

Avrahami

Klochendler²,

Dor³

et al. 2017

Diabetologia

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Beta cells are primarily defined by their ability to produce insulin and secrete it in response to appropriate stimuli. It has been known for some time, however, that beta cells are not functionally identical to each other and that the rates of insulin synthesis and release differ from cell to cell, although the functional significance of this variability remains unclear. Recent studies have used heterogeneous gene expression to isolate and evaluate different subpopulations of beta cells and to demonstrate alterations in these subpopulations in diabetes. In the last few years, novel technologies have emerged that permit the detailed evaluation of the proteome (e.g. time-of-flight mass spectroscopy, [CyTOF]) and transcriptome (e.g. massively parallel RNA sequencing) at the single-cell level, and tools for single beta cell metabolomics and epigenomics are quickly maturing. The first wave of single beta cell proteome and transcriptome studies were published in 2016, giving a glimpse into the power, but also the limitations, of these approaches. Despite this progress, it remains unclear if the observed heterogeneity of beta cells represents stable, distinct beta cell types or, alternatively, highly dynamic beta cell states. Here we provide a concise overview of recent developments in the emerging field of beta cell heterogeneity and the implications for our understanding of beta cell biology and pathology.

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Section: Multihormonal Islet Cellsmentioning

confidence: 79%

Beta cell heterogeneity: an evolving concept

Avrahami

Klochendler²,

Dor³

et al. 2017

Diabetologia

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“…Indeed, following a nearly total β‐cell ablation in mice, α‐ and δ‐cells were reported to acquire β‐cell identity . Furthermore, in diabetic rodent and human islets sub‐populations of β‐ and δ‐cells start expressing the foetal islet hormone gastrin …”

Section: Zooming Into the Pancreatic Islet Clock: Molecular Oscillatomentioning

confidence: 90%

“…110,111 Furthermore, in diabetic rodent and human islets sub-populations of βand δ-cells start expressing the foetal islet hormone gastrin. 112 The well-established heterogeneity of endocrine islet cell types and evolving evidence on sub-type diversity within these populations bring another layer of complexity into the assessment of islet cell molecular clocks. Future directions in this context will unravel whether the molecular makeup of circadian oscillators differs between distinct islet cell populations, sub-populations and individual cells;…”

Section: Islet Cell Heterogeneity: Do Molecular Clock Properties DImentioning

confidence: 99%

Time zones of pancreatic islet metabolism

Petrenko

Philippe

Dibner

2018

Diabetes Obesity Metabolism

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Most living beings possess an intrinsic system of circadian oscillators, allowing anticipation of the Earth's rotation around its own axis. The mammalian circadian timing system orchestrates nearly all aspects of physiology and behaviour. Together with systemic signals originating from the central clock that resides in the hypothalamic suprachiasmatic nucleus, peripheral oscillators orchestrate tissue-specific fluctuations in gene transcription and translation, and posttranslational modifications, driving overt rhythms in physiology and behaviour. There is accumulating evidence of a reciprocal connection between the circadian oscillator and most aspects of physiology and metabolism, in particular as the circadian system plays a critical role in orchestrating body glucose homeostasis. Recent reports imply that circadian clocks operative in the endocrine pancreas regulate insulin secretion, and that islet clock perturbation in rodents leads to the development of overt type 2 diabetes. While whole islet clocks have been extensively studied during the last years, the heterogeneity of islet cell oscillators and the interplay between α- and β-cellular clocks for orchestrating glucagon and insulin secretion have only recently gained attention. Here, we review recent findings on the molecular makeup of the circadian clocks operative in pancreatic islet cells in rodents and in humans, and focus on the physiologically relevant synchronizers that are resetting these time-keepers. Moreover, the implication of islet clock functional outputs in the temporal coordination of metabolism in health and disease will be highlighted.

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“…Similarly, loss of Wfs1 in mouse β cells leads to ER stress, loss of GSIS, and eventual cell death (44,45). Recent work on the expression of fetal hormone gastrin in diabetic β cells shows that unlike fetal development, gastrin reexpression in diabetes does not involve Neurogenin3 (46). Thus, while metabolic stress can alter adult β cell identity, such that these cells express fetal-like features, the molecular pathways utilized may be different from fetal development.…”

Section: Discussionmentioning

confidence: 99%